Delta opioid receptor upregulation;a new model to examine the effects of cocaine. ?-arrestin 1, a scaffolding protein, regulates the persistence of cocaine seeking so that mice lacking this protein continue to prefer a cocaine-associated environment even after cocaine has been withdrawn. The genetic deletion of ? -arrestin 1 increases the function of the delta opioid receptor by altering the reorganization of the 3-dimensional actin cytoskeleton in neurons of the nociceptive pathway. It is possible that a similar upregulation of delta receptor function in neurons of the mesolimbic dopaminergic reward system explains the persistence of cocaine seeking seen in mice lacking ? -arrestin 1. This application will examine whether such upregulation does occur in these neurons and if so, whether the actin cytoskeleton is involved (Specific Aim 1). Furthermore, the role of the delta receptor in the sensitization to cocaine and persistence of cocaine seeking will be assessed in mice lacking both ? -arrestin 1 and the delta opioid receptor (Specific Aim 2). As the role of the delta receptor in the behavioral response to drugs of abuse has proved elusive to examine, such functional upregulation of the delta receptor may provide a novel and innovative method of assessing how the delta receptor may affect the behaviors associated with drugs of abuse. PUBLIC HEALTH RELEVANCE: Understanding the role of the opioids in the response to drugs of abuse such as cocaine is an important step in preventing drug abuse. This application will define a model system to examine how one of these opioids is involved in the response to cocaine.